Mouse models of colorectal cancer: Past, present and future perspectives

Abstract

Colorectal cancer (CRC) is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union. While the incidence and mortality rates in western, high developed countries are declining, reflecting the success of screening programs and improved treatment regimen, a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index. Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades, preclinical in vivo models are still indispensable for the development of new treatment approaches. Since the development of carcinogen-induced rodent models for CRC more than 80 years ago, a plethora of animal models has been established to study colon cancer biology. Despite tenuous invasiveness and metastatic behavior, these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis. Genetically engineered mouse models (GEMM) mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited. Although the vast majority of CRC GEMM lack invasiveness, metastasis and tumor heterogeneity, they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses; thus, supporting development of new therapeutic avenues. Induction of metastatic disease by orthotopic injection of CRC cell lines is possible, but the so generated models lack genetic diversity and the number of suited cell lines is very limited. Patient-derived xenografts, in contrast, maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development - even in comparison to GEMM or cell line-based analyses. However, subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses. The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models.

Keywords: Carcinogen-induced models; Colorectal cancer; Genetically engineered mouse models; Mouse models; Patient-derived xenografts; Preclinical drug development.

Figure 1

Overview of the frequently altered pathways in colorectal cancer. The numbers in square brackets label the corresponding model descriptions as given in Table 1.

Figure 2

Establishment of PDX. After surgery, a small sample of the tumor, which is not needed for pathological diagnosis, is obtained and cut into pieces of 27 mm³. These can be either implanted immediately in recipient mice or vitally cryopreserved in liquid nitrogen. The resulting patient-derived xenograft (b) closely reflects the histology of the donor tumor (a) (Previously published in[229]). Patient-derived xenograft can be further processed for subsequent implantation or cryopreservation.